The fate of ritonavir in the presence of darunavir.

This study was the first investigation into the potential of a fixed dose combination of ritonavir and darunavir in the form of dispersible powders prepared by spray drying. A common polymer (hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone-vinyl acetate 64) was formulated with either ritonavir or darunavir or a combination of ritonavir and darunavir. The influence of these polymers on the supersaturation level of ritonavir and darunavir was investigated. The concentration levels of ritonavir and darunavir during these tests dropped instantly to a plateau which could be considered as amorphous solubility. Besides, the presence of darunavir always decreased the supersaturation level of ritonavir and vice versa no matter which polymers were used. Moreover, the rate and extent of release of both ritonavir and darunavir from ternary spray-dried powders were less than the releases from binary spray-dried powders. Intermolecular interaction between ritonavir and darunavir was ruled out by (1)H NMR study which means that the decrease in supersaturation level or release must be at least partially attributed to the mediated solvent process. In order to restrict the mutual influence between darunavir and ritonavir, a complex of both ritonavir and darunavir with (2-hydroxypropyl)-ß-cyclodextrin was prepared and improved the dissolution rate of both ritonavir and darunavir.

Eudragit E PO as a complementary material for designing oral drug delivery systems with controlled release properties: comparative evaluation of new interpolyelectrolyte complexes with countercharged eudragit L100 copolymers.

The design of new interpolyelectrolyte complexes (IPEC) between countercharged polymers (Eudragit EPO (EPO) and Eudragit L100 (L100)) was investigated. The formation and chemical composition of three new IPECs between EPO and L100 was established by elemental analysis. The structure and solid state properties of the synthesized IPEC were investigated using Fourier transform infrared (FTIR) spectroscopy and modulated temperatre differential scanning calorimetry (MTDSC). The binding ratio of a unit molecule of EPO with L100 was found to range between 1:0.98 (Z = 1.02) and 1:0.50 (Z = 2.00) while increasing the pH from 6.0 to 7.0. As a result of electrostatic interaction between the copolymer chains, the glass transition temperature of the IPEC increased significantly. Considerable pH-sensitive swelling in acidic and neutral media was observed for different type of IPECs. Through evaluation of diffusion-transportation properties of the IPECs, basic mechanisms controlling the delivery of chemically different drugs (diclofenac sodium and theophylline) were obtained. The results of swelling and release of the model drugs from the polycomplex matrices confirm that they have potential to be used in oral controlled drug delivery.

Solid state solubility of miconazole in poly[(ethylene glycol)-g-vinyl alcohol] using hot-melt extrusion.

The use of hot-melt extrusion for preparing homogeneous API-excipient mixtures is studied for miconazole-PEG-g-PVA [poly(ethylene glycol)-poly(vinyl alcohol) graft copolymer] solid dispersions with a 5 cm(3) table-top, twin-screw corotating microcompounder (DSM Xplore). Phase behavior of PEG-g-PVA, miscibility of miconazole in PEG-g-PVA and the partitioning of miconazole between PEG and PVA amorphous phases are characterized using a combination of modulated DSC, XRPD, and solid-state (1)H and (13)C NMR methods. The (1)H NMR transverse magnetization relaxation (T(2) relaxation) method is used to analyze the phase composition and molecular mobility of the copolymer. The T(2) relaxation decay of pure PEG-g-PVA can be described by four T(2) relaxation components in the temperature range studied. PVA crystallinity is not largely affected by hot-melt extrusion and the presence of the drug. Miconazole preferably resides in the PEG amorphous phase, and its molecules are well dispersed in the PEG-g-PVA matrix using hot-melt extrusion mixing. Miconazole forms amorphous nanoclusters whose average size equals approximately 1.6 nm, indicating solid solution formation (molecular level dispersion) of the drug in the polymer.

PLGA nanoparticles and nanosuspensions with amphotericin B: Potent in vitro and in vivo alternatives to Fungizone and AmBisome.

This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) and nanosuspensions with the polyene antibiotic amphotericin B (AmB). The nanoformulations were prepared using nanoprecipitation and were characterised with respect to size, zeta potential, morphology, drug crystallinity and content. Standard in vitro sensitivity tests were performed on MRC-5 cells, red blood cells, Leishmania infantum promastigotes and intracellular amastigotes and the fungal species Candida albicans, Aspergillus fumigatus and Trichophyton rubrum. The in vivo efficacy was assessed and compared to that of Fungizone and AmBisome in the acute A. fumigatus mouse model at a dose of 2.5 and 5.0mg/kg AmB equivalents. The developed AmB nanoformulations were equivalently or more effective against the different Leishmania stages and axenic fungi in comparison with the free drug. The in vitro biological activity, and especially hemolytic activity, clearly depended on the preparation parameters of the different nanoformulations. Further, we demonstrated that the superior in vitro antifungal activity could be extrapolated to the in vivo situation. At equivalent dose, the optimal AmB-loaded PLGA NP was about two times and the AmB nanosuspension about four times more efficacious in reducing the total burden than AmBisome. The developed AmB nanomedicines could represent potent and cost-effective alternatives to Fungizone and AmBisome.

Solution calorimetry as an alternative approach for dissolution testing of nanosuspensions.

The formulation of poorly soluble drugs as nanocrystals/nanosuspensions has rapidly evolved during the past decade into a mature drug-delivery strategy. The major characteristic of these systems is the high drug dissolution rate, enabling bioavailability enhancement after oral administration. It is therefore of great importance to have access to analytical methodology that is able to accurately monitor the extreme fast dissolution process of such formulations. The aim of the present study was to evaluate solution calorimetry as a novel approach to measure the dissolution rate of nanosuspensions by recording the temperature change in the dissolution vessel during the dissolution process of the nanocrystals. The applicability was tested on different nanosuspensions made up of three model drugs: naproxen, cinnarizine and an investigational API, i.e. compound A. The dissolution process of all nanosuspensions investigated was completed within less than 1 min. During this period, sufficient data points were collected to transform temperature offset data to cumulative heat of solution pointing to the potential of this technique. However, of significant concern is the fact that this technique measures the total heat produced or consumed by all processes that occur during the dissolution, e.g. the heat of mixing when the nanosuspension comes in contact with the dissolution medium. Erroneous conclusions will result if phenomena other than dissolution are not accounted for.

Potential of amorphous microporous silica for ibuprofen controlled release.

Amorphous microporous silica (AMS) xerogel materials were synthesized in an acid-catalyzed sol-gel process. The porosity of AMS was adapted by varying sol-gel synthesis parameters including the molar hydrolysis ratio (r-value), HCl:Si molar ratio, the type of silicon alkoxide source and the solvent. AMS particles of millimeter size were loaded with ibuprofen, by heat treatment and melt impregnation. In vitro release experiments were performed in simulated gastric and intestinal fluid. The release kinetics were critically depending on the AMS particle size distribution and the micropore diameter. The release was interpreted as configurational diffusion in the AMS micropores. The stability of unloaded and ibuprofen loaded AMS material upon storage was investigated using nitrogen physisorption, DSC analysis and in vitro release experiments. Ibuprofen loaded AMS formulations show remarkable stability, which can be attributed to the presence of ibuprofen molecules in the channels, functioning as scaffolds to support the pore structure.

Modeling drug release from hot-melt extruded mini-matrices with constant and non-constant diffusivities.

Different types of ethylcellulose-based mini-matrices were prepared by hot-melt extrusion and thoroughly characterized in vitro. Metoprolol tartrate was used as model drug, and various amounts and types of polyethylene glycol (PEG)/polyethylene oxide (PEO) were added as release rate modifiers. Based on the experimental results, appropriate mathematical theories were identified/developed, allowing for a better understanding of the underlying drug release mechanisms. For instance, it could be shown that at high initial PEG/PEO contents and/or intermediate initial PEG/PEO contents of low molecular weight, drug diffusion with time- and position-independent diffusivities is predominant. In contrast, at low initial PEG/PEO contents and intermediate initial PEG/PEO contents of high molecular weight, the time- and position-dependent dynamic changes in the matrix porosities significantly affect the conditions for drug and PEG/PEO diffusion. These dynamic changes must be taken into account in the mathematical model. Importantly, the proposed theories are mechanistic realistic and also allow for the quantitative prediction of the effects of the device design on the resulting drug release patterns. Interestingly, these quantitative predictions could be confirmed by independent experiments. Furthermore, Raman spectroscopy allowed for the determination of the resulting drug concentration-position profiles within the mini-matrices as a function of time and confirmed the theoretical predictions.

Influence of polyethylene glycol/polyethylene oxide on the release characteristics of sustained-release ethylcellulose mini-matrices produced by hot-melt extrusion: in vitro and in vivo evaluations.

Over the last few decades, polysaccharides have gained increasing attention in the biomedical and drug delivery fields. Among them, glucomannan (GM), has become a particularly attractive polymer. In this paper, we review the physicochemical and biological properties which are decisive for the exploitation of GM as a biomaterial. These properties include the structural organization, molecular weight, solubility, viscosity, gelling properties and degradation behavior. Moreover, herein we analyze the possibilities of combining GM with other hydrophilic polymers, as well as the preparation of semisynthetic derivatives of GM, which may be of interest in the pharmaceutical context. Finally, we discuss the specific applications of GM in the drug delivery field.

Development of a liquid chromatographic assay for an anti-HIV tablet containing lamivudine, zidovudine and TMC278.HCL.

A liquid chromatographic method was developed to analyse a tablet containing three anti-human immunodeficiency virus (HIV) compounds: lamivudine, zidovudine and a compound with the code name TMC278.HCl. Due to the presence of UV absorbing chromophores in the three active components, a single LC method with UV detection was developed. A Hypersil BDS C(18) column was used as stationary phase and the assay was performed with gradient elution using mobile phases containing acetonitrile, 0.2M potassium dihydrogen phosphate and water. The sample pretreatment is performed by treating the formulation with dimethyl sulfoxide-water (1:1) followed by filtration. After method development, the influence of the different chromatographic parameters on the separation, the interference of other active compounds and excipients, the repeatability and the linearity were investigated. The method was shown to be robust, selective, linear and repeatable. Finally, the content of the compounds in the tablet was determined.

Dissolution enhancement of the anti-HIV drug UC 781 by formulation in a ternary solid dispersion with TPGS 1000 and Eudragit E100.

The present research deals with the improvement of the dissolution properties of the anti-HIV drug UC 781. A ternary solid dispersion consisting of a high amount of TPGS 1000 and exhibiting good powder properties with respect to flowability was developed. Eudragit E100 was selected as a polymer based on supersaturation studies. DSC analysis of solid dispersions containing drug doses from 0 to 80% w/w revealed eutectic phase behaviour of the ternary TPGS 100-Eudragit E100-UC 781 mixture. The release of UC 781 in a medium simulating the gastrointestinal lumen was markedly enhanced, reaching a release of 70% w/w after 4h. XRD results pointed to the presence of crystalline drug in the solid dispersion. The presence of UC 781 in the dispersion had an influence on the TPGS 1000-Eudragit E100 carrier, favoring folding of the polyethylene glycol chains in TPGS 1000. Moreover, the addition of UC 781 to the binary polymer-surfactant mixture was physically expressed by an increase in fluidity of the samples up to a drug load of 50% w/w. NMR was used to investigate this phenomenon, revealing a shielding and/or deshielding effect of the carrier on aromatic C atoms and methyl groups in UC 781. Polyethylene glycol chains present in TPGS 1000 seemed to play a role in this process. In addition, combining UC 781 with the TPGS 1000-Eudragit E100 mixture led to the appearance of TPGS 1000 clusters with a glass transition temperature well below the T(g)'s of the pure compounds.

Pharmaceutical aspects of drug eluting stents.

This review focuses on the pharmaceutical aspects of the development of drug eluting stents. It discusses the different processes that can be used to obtain a controlled release of a drug from the stent as well as the coatings therefore applied. Results obtained for stents already available on the market or in a far stage of development are discussed. In a final part possible future research areas as well as expected new evolutions in the design of drug eluting stents are presented.

Influence of formulation and process parameters on the release characteristics of ethylcellulose sustained-release mini-matrices produced by hot-melt extrusion.

Mini-matrices (multiple unit dosage form) with release-sustaining properties were developed by hot-melt extrusion (cylindrical die: 3mm) using metoprolol tartrate as model drug and ethylcellulose as sustained-release agent. Dibutyl sebacate was selected as plasticizer and its concentration was optimized to 50% (w/w) of the ethylcellulose concentration. Xanthan gum, a hydrophilic polymer, was added to the formulation to increase drug release. Changing the xanthan gum concentration modified the in vitro drug release: increasing xanthan gum concentrations (1%, 2.5%, 5%, 10% and 20%, w/w) yielded a faster drug release. Zero-order drug release was obtained at 5% (w/w) xanthan gum. Using kneading paddles, smooth extrudates were obtained when processed at 60 degrees C. At least one mixing zone was required to obtain smooth and homogeneous extrudates. The mixing efficacy and drug release were not affected by the number of mixing zones or their position along the extruder barrel. Raman analysis revealed that metoprolol tartrate was homogeneously distributed in the mini-matrices, independent of screw design and processing conditions. Simultaneously changing the powder feed rate (6-25-50 g/min) and screw speed (30-100-200 rpm) did not alter extrudate quality or dissolution properties.

Characterization of physico-chemical properties and pharmaceutical performance of sucrose co-freeze-dried solid nanoparticulate powders of the anti-HIV agent loviride prepared by media milling.

In order to improve the dissolution and absorption properties of loviride, a poorly soluble antiviral agent, sucrose co-freeze-dried nanopowders were prepared, characterized and evaluated. Tween 80/poloxamer 188-stabilized nanosuspensions were produced on a laboratory scale using media milling. The milling process was monitored by dynamic light scattering (DLS) and resulted in particles with a mean size of 264+/-14nm and a distribution width of 59+/-6nm after 4h of milling. Co-freeze-drying of the nanosuspensions with sucrose had an inhibiting effect on nanoparticle agglomeration and yielded solid "nanopowders" that were resuspendable and homogeneous with respect to loviride content. X-ray powder diffraction (XRPD) confirmed the presence of small loviride crystallites and indicated that sucrose and poloxamer 188 were crystalline. Differential scanning calorimetry (DSC) showed melting peaks of poloxamer 188, sucrose and loviride. Time-resolved XRPD indicated that sucrose crystallization was complete within 24h of storage. Scanning electron microscopy (SEM) suggested the formation of sheet-like matrix structures. The dissolution rate of loviride from the nanopowders was excellent. A Caco-2 experiment on the nanopowder showed a significantly higher cumulative amount transported after 120min (1.59+/-0.02microg) compared to the physical mixture (0.93+/-0.01microg) and the untreated loviride (0.74+/-0.03mcirog).

Correlation between digestion of the lipid phase of smedds and release of the anti-HIV drug UC 781 and the anti-mycotic drug enilconazole from smedds.

The present studies were conducted primarily to compare the drug release process of the anti-HIV drug UC781 from three different smedds to the smedds digestion profile. The influence of every formulation component on the digestion process, measured as the release of fatty acids, was determined. In addition, the release of the antimycotic drug enilconazole from a smedds was investigated as well in order to study the influence of the type of incorporated drug on oil digestion. Simulsol 1292, Tween 80, Cremophor RH40, ethanol and both drugs reduced the fatty acid release. C8, C10 and C12 fatty acids, originating from oil hydrolysis, were able to reverse the inhibitory effect of phospholipids present in the release medium. Similarly Cremophor RH40 lost its inhibitory capacities in combination with Captex 200P hydrolysis. In addition, UC781 did not decrease fatty acid release in combination with a Captex 200P-Tween 80-ethanol mixture. The release of UC781 from smedds significantly increased compared to the dissolution of the pure drug. The drug release profiles were characterized by rapid and complete release followed by precipitation. In order to detect possible correlations between drug release and oil digestion, release results were compared to those of vehicle digestion experiments. Contrary to what one would assume, a higher extent of fatty acid liberation did not enhance drug release. In other words, drug release does not seem to be driven by the extent of lipid digestion.

Light scattering measurements on microemulsions: estimation of droplet sizes.

Different scattering methods were used as tools to assess the size of droplets in highly diluted microemulsions. These were obtained after dilution of a self-emulsifying system made up of an oil, a surfactant and ethanol. Typical methods, often used in size and shape determination of particles, such as SAXS and USAXS suffer in the present case from a lack of electrondensity contrast. It becomes clear from our extensive use of dynamic light scattering that one should be careful in interpreting the latter data as well. Sample preparation and the subsequent handling of the samples during the experiments strongly affect reproducibility of the results. There is a need for well-defined protocols at the level of sample preparation and data handling. In the present research one uses extensively dynamic light scattering (DLS) in the back scattering mode and strengths and pitfalls, inherent to the backscattering technique, are discussed. It is crucial to be aware of droplet size distributions (monomodal/bimodal/multimodal) while reporting mean radii (Rh) as this radius is only relevant in the case of well-defined monomodal distributions. Moreover, one should asses the shape of the droplets prior to data interpretation, as usual in scattering methods, by an independent method. Anyway the shape of the time correlation functions of the scattered intensity should be reported or at least inspected as they provide information on the reproducibility of the experiments hence safegarding the value of the physical meaning of the final value of droplet size (Rh). Preferentially static light scattering (SLS) measurements should always support DLS experiments as the angular dependence is very sensitive to the presence of large particles.

Characteristics of interpolyelectrolyte complexes of Eudragit E 100 with sodium alginate.

With a view to the application in oral drug delivery formulations, the possibility to form interpolyelectrolyte complexes (IPEC) of Eudragit E 100 (EE) with sodium alginate (AL) was investigated, employing turbidimetry, apparent viscosity measurements, FT-IR and elementary analysis. The interaction or binding ratio of a unit molecule of AL with EE was largely affected by the pH value of the media, showing a change from 1.5:1 to 1:1.25 (0.66

Characteristics of interpolyelectrolyte complexes of Eudragit E100 with Eudragit L100.

With a view to the application in oral controlled drug delivery systems, the formation of interpolyelectrolyte complexes (IPEC) between Eudragit E100 (EE) and Eudragit L100 (EL) was investigated, using turbidimetry, solution viscosity measurements and elementary analysis. The structure of the synthesized IPEC was investigated by using FT-IR spectroscopy. The binding ratio of a unit molecule of EL with EE was found to be approximately 1:1 in pH 6.0. Based on the results of elementary analysis, and FT-IR, the binding ratio of each component in the solid complexes was very close to that observed in turbidity and viscosity measurements and indicate that the synthesized products can be considered as IPEC. Due to the structure of the IPEC, two maxima were observed in the swelling behaviour as a function of pH. The release of the model drug ibuprofen was significantly retarded from tablets made up of the IPEC.

In vivo evaluation of a colonic delivery system using isotope techniques.

AIM: To evaluate, using isotope techniques, the in vivo effectiveness of a pH-dependent colonic delivery system. METHODS: In order to dispose of differently labelled substrates for measurement of orocaecal transit time, inulin-14C-carboxylic acid was evaluated as an alternative substrate to inulin and lactose-13C-ureide. Secondly, the time of release of 13C- and 15N-urea from the colonic delivery system was compared with the orocaecal transit time, measured using inulin and inulin-14C-carboxylic acid. This study was repeated after a 2-week lactulose intake period. RESULTS: The orocaecal transit time determined using inulin-14C-carboxylic acid (398 min) was not significantly different from the orocaecal transit time determined using inulin (420 min) or lactose-13C-ureide (396 min). Before lactulose intake, the 13CO2 excretion time was 358 min and the orocaecal transit times determined with the inulin-14C-carboxylic acid and inulin breath test were 376 and 375 min respectively. After lactulose, the 13CO2 excretion time was 383 min and orocaecal transit times were 354 min for inulin-14C-carboxylic acid and 392 min for inulin. A highly significant correlation was found. Good agreement was found between the urinary 15N excretion and the appearance of 13CO2 in breath. CONCLUSION: Isotope techniques provide an excellent non-invasive tool for the in vivo evaluation of a colonic delivery system.

Evaluation of different calorimetric methods to determine the glass transition temperature and molecular mobility below T(g) for amorphous drugs.

The purpose of the present study was to compare different calorimetric methods used to determine the glass transition temperature (T(g)) and to evaluate the relaxation behaviour and hence the stability of amorphous drugs below their T(g). Data showed that the values of the activation energy for the transition of a glass to its super-cooled liquid state qualitatively correlate with the values of the mean molecular relaxation time constant of ketoconazole, itraconazole and miconazole, three structurally related drugs. Estimation of the molecular mobility by activation energy calculation indicated that loperamide was more stable than its two building blocks T263 and R731. It was further shown that the most commonly used approach to determine T(g) (T(g (1/2 c(p))) leads to erroneous values when enthalpy recovery is significant. In this case, an alternative method based on enthalpic considerations leads to results in accordance to basic thermodynamics. Estimation of molecular mobility based on activation energy calculations is therefore considered to be a valuable alternative for the method based on measurement of the extent of relaxation. When enthalpy relaxation is important, the use of T(g 1/2c(p)) leads to an overestimation of the T(g).

Improvement of the dissolution rate of artemisinin by means of supercritical fluid technology and solid dispersions.

The purpose of this study was to enhance the dissolution rate of artemisinin in order to improve the intestinal absorption characteristics. The effect of: (1) micronisation and (2) formation of solid dispersions with PVPK25 was assessed in an in vitro dissolution system [dissolution medium: water (90%), ethanol (10%) and sodium lauryl sulphate (0.1%)]. Coulter counter analysis was used to measure particle size. X-ray diffraction and DSC were used to analyse the physical state of the powders. Micronisation by means of a jet mill and supercritical fluid technology resulted in a significant decrease in particle size as compared to untreated artemisinin. All powders appeared to be crystalline. The dissolution rate of the micronised forms improved in comparison to the untreated form, but showed no difference in comparison to mechanically ground artemisinin. Solid dispersions of artemisinin with PVPK25 as a carrier were prepared by the solvent method. Both X-ray diffraction and DSC showed that the amorphous state was reached when the amount of PVPK25 was increased to 67%. The dissolution rate of solid dispersions with at least 67% of PVPK25 was significantly improved in comparison to untreated and mechanically ground artemisinin. Modulation of the dissolution rate of artemisinin was obtained by both particle size reduction and formation of solid dispersions. The effect of particle size reduction on the dissolution rate was limited. Solid dispersions could be prepared by using a relatively small amount of PVPK25. The formation of solid dispersions with PVPK25 as a carrier appears to be a promising method to improve the intestinal absorption characteristics of artemisinin.